Preparation of risperidone

ABSTRACT

The present invention is directed to the novel forms of risperidone, designated Form A, Form B and Form E. Methods for their preparation are also disclosed. The present invention also relates to processes for making risperidone. Pharmaceutical compositions containing the new forms of risperidone and methods of using them are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of provisional application Ser. No.60/225,361, filed Aug. 14, 2000; and provisional application Ser. No.60/243,263, filed Oct. 25, 2000. Both of these applications areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel polymorphic forms of risperidone.The present invention also relates to methods of making polymorphicforms of risperidone.

BACKGROUND OF THE INVENTION

RISPERDAL® (risperidone) is an antipsychotic agent belonging to a newchemical class, the benzisoxazole derivatives. The chemical designationis3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.

U.S. Pat. No. 4,804,663, the contents of which are incorporated byreference, describes a synthesis of risperidone. Risperidone may beprepared by condensation of the following two intermediates,6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I) and3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(Compound II) in dimethylformamide (DMF) in basic conditions (Na₂CO₃ orK₂CO₃) with catalytic amount of potassium iodide (KI). The cruderisperidone product (III) is crystallized from a mixture of DMF andisopropanol with an overall yield of 46%.

Polymorphism is the occurrence of different crystalline forms of asingle compound and it is a property of some compounds and complexes.Thus, polymorphs are distinct solids sharing the same molecular formula,yet each polymorph may have distinct physical properties. Therefore, asingle compound may give rise to a variety of polymorphic forms whereeach form has different and distinct physical properties, such asdifferent solubility profiles, different melting point temperaturesand/or different x-ray diffraction peaks. Since the solubility of eachpolymorph may vary, identifying the existence of pharmaceuticalpolymorphs is essential for providing pharmaceuticals with predicablesolubility profiles. It is desirable to investigate all solid stateforms of a drug, including all polymorphic forms, and to determine thestability, dissolution and flow properties of each polymorphic form.Polymorphic forms of a compound can be distinguished in a laboratory byX-ray diffraction spectroscopy and by other methods such as, infraredspectrometry. For a general review of polymorphs and the pharmaceuticalapplications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J.K. Haleblian and W. McCrone, J Pharm. Sci., 58, 911 (1969); and J. K.Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which areincorporated herein by reference.

SUMMARY OF THE INVENTION

An object of the processes of the present invention is to provide moreefficient and quicker methods for making pure risperidone. We have nowfound that the synthesis of risperidone from compounds I and II can donein acetonitrile and isopropanol, without using DMF, to give an improvedand higher yield of about 75%.

The present invention provides a process for the preparation ofrisperidone from the following two intermediates,6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I) and3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(Compound II) in acetonitrile.

It has also been found that the crude risperidone can be efficientlycrystallized in high yield from an alcohol, for example, isopropanol,butanol, ethanol, or methanol; or from a ketone, for example, acetone orethyl methyl ketone, without the need of using DMF, which is harmful tohumans and is a very difficult solvent to remove.

Polymorphs of risperidone are mentioned in the Summary Basis of Approval(SBA) of New Drug Application 20-272 and 20-588, however the SBA doesnot identify them by recognized methods of crystal structureidentification such as x-ray diffraction.

The present invention also provides forms of risperidone designatedrisperidone Form A, Form B and Form E.

The present invention further provides a process for making risperidonecomprising reacting Compound I with Compound II to form cruderisperidone (III) in a solvent selected from the group consisting ofacetonitrile, isopropanol, methyl ethyl ketone and iso-butanol.

In another embodiment, the crude risperidone is recrystallized from analcohol; a mixture of alcohols; a mixture of water and alcohol; or froma ketone, e.g., acetone. In another embodiment, the alcohol is selectedfrom the group consisting of methanol, ethanol, isopropanol, propanol,butanol, sec-butanol, iso-butanol and t-butanol. In another embodiment,the alcohol is isopropanol. In another embodiment, the alcohol isacetonitrile. In another embodiment, the alcohol is isopropanol. Inanother embodiment, the alcohol is iso-butanol. In another embodiment,the ketone is acetone. In another embodiment, the acetone is methylethyl ketone.

The present invention also provides risperidone Form A which ischaracterized by x-ray powder diffraction peaks at 14.2±0.2, 21.3±0.2degrees two-theta. The present invention also provides risperidone FormA of further characterized by x-ray powder diffraction peaks at10.6±0.2, 11.4±0.2, 16.4±0.2, 18.9±0.2, 19.9±0.2, 22.5±0.2, 23.3±0.2,25.4±0.2, 27.6±0.2, 29.0±0.2 degrees two-theta.

The present invention also provides a risperidone polymorph that ischaracterized by a powder x-ray diffraction pattern substantially asdepicted in FIG. 1.

The present invention also provides risperidone Form B which ischaracterized by x-ray powder diffraction peaks at 14.0±0.2 and 21.7±0.2degrees two-theta.

The present invention also provides a risperidone polymorph that ischaracterized by a powder x-ray diffraction pattern substantially asdepicted in FIG. 2.

The present invention also provides risperidone Form B which is furthercharacterized by x-ray powder diffraction peaks at 10.8±0.2, 11.9±0.2,12.6±0.2, 14.0±0.2, 17.5±0.2, 18.3±0.2, 19.9±0.2, 21.0±0.2, 21.7±0.2degrees two-theta.

The present invention also provides risperidone Form E which ischaracterized by x-ray powder diffraction peaks at 16.5±0.2, 21.7±0.2degrees two-theta.

The present invention also provides risperidone Form E which is furthercharacterized by x-ray powder diffraction peaks at 16.5±0.2, 12.6±0.2,21.7±0.2, 15.6±0.2, 17.0±0.2, 18.4±0.2, 19.1±0.2, 21.3±0.2, 24.0±0.2,24.9±0.2, 27.0±0.2 degrees two-theta.

The present invention also provides a risperidone polymorph that ischaracterized by a powder x-ray diffraction pattern substantially asdepicted in FIG. 3.

The present invention also provides a process for preparing risperidoneForm B comprising the steps of: dissolving risperidone in asubstantially water soluble alcohol having 1 to 4 carbon atoms where theratio of risperidone to alcohol is about 1:7.5 to about 1:9; addingwater to facilitate precipitation; and isolating risperidone Form B.

The present invention also provides a process for preparing risperidoneForm B comprising the steps of: dissolving risperidone in chloroform;adding cyclohexane or hexane to facilitate precipitation; and isolatingrisperidone Form B.

The present invention also provides a process for preparing risperidoneForm B comprising the steps of: dissolving risperidone in an aqueoussolution of HCl; adding an aqueous solution of Na₂CO₃; and isolatingrisperidone Form B.

The present invention also provides a process for preparing risperidoneForm A comprising the steps of: dissolving risperidone in an organicsolvent selected from the group consisting of dimethylformamide,tetrahydrofuran, acetone, benzene, ethyl methyl ketone, n-butanol,methanol, isopropanol, absolute ethanol, acetonitrile, toluene, dimethylsulfoxide, iso-butanol, and ethyl acetate or mixtures thereof; heatingthe solvent to reflux; cooling the solvent to facilitate precipitation;and isolating risperidone Form A.

The present invention also provides a process for preparing risperidoneForm A comprising the steps of: dissolving risperidone indichloromethane; adding cyclohexane or hexane to facilitateprecipitation; and isolating risperidone Form A.

The present invention also provides a method for preparing risperidoneForm A comprising the step of: heating risperidone Form B at atemperature of about 25° C. to about 80° C. for a time sufficient toinduce to formation of risperidone Form A; and isolating risperidoneForm A. In another embodiment, the heating takes place under reducedpressure or at atmospheric pressure. In another embodiment, thetemperature is about 80° C. In another embodiment, the time for heatingis about 16 to about 20 hours.

The present invention also provides a process for preparing risperidoneForm E comprising the steps of: dissolving risperidone in isopropanolwhere the ratio of risperidone to isopropanol is about 1:12; addingwater to facilitate precipitation; and isolating risperidone Form E.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a characteristic x-ray powder diffraction spectrum ofrisperidone Form A.

FIG. 2 is a characteristic x-ray powder diffraction spectrum ofrisperidone Form B.

FIG. 3 is a characteristic x-ray powder diffraction spectrum ofrisperidone Form E.

DETAILED DESCRIPTION OF THE INVENTION

Synthesis of Risperidone

The present invention provides new processes for preparing risperidonefrom the following two intermediates,6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (I) and3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(II) using acetonitrile, isopropanol, iso-butanol, or methyl ethylketone as the solvent, which eliminates the need to use DMF as asolvent. By the methods of the present invention, risperidone isprepared by adding,3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H1-pyrido[1,2-a]pyrimidin-4-one(Compound II or “the chlorine derivative”);6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I or “thepiperidine derivative”); sodium carbonate; and potassium iodide (66 mg)into a flask containing the solvent isopropanol, acetonitrile, methylethyl ketone or iso-butanol. Preferably, the Compound I and Compound IIare present in a ratio of about 1:1. The reaction mixture is then heatedby methods known in the art, such as, by placing the flask in an oilbath which is heated from about 60° C. to about 85° C., and the reactionis allowed to reflux for a time sufficient to complete the formation ofrisperidone, about 9 hours to overnight. Preferably, the reactionmixture is heated to about 60° C. to about 67° C. Preferably thereaction is heated for about 9 hours when the solvent is isopropanol.Preferably the reaction mixture is heated overnight when the solvent ismethyl ethyl ketone or iso-butanol. Preferably the reaction is heatedfor about 17 hours when the solvent is acetonitrile. Upon completion ofthe reaction, the mixture is cooled by methods known in the art toinduce the precipitation of risperidone.

The resulting precipitated risperidone is filtered and the filter cakeis washed in the filter with a small amount of isopropanol, acetone or amixture of acetone and water. The filter cake is then slurried, filteredand easily dried by conventional methods to give crude risperidone in ayield of about 63 to 74% yield. The present method eliminates thedifficult step of removing DMF from the crude risperidone.

The present invention also relates to new processes for recrystallizingcrude risperidone from; an alcohol, such as, methanol, ethanol,isopropanol, propanol, butanol, sec-butanol and t-butanol; a mixture ofalcohols containing any combination of, methanol, ethanol, isopropanol,propanol, butanol, sec-butanol and t-butanol; or a mixture of water andalcohol where the alcohol is one or more of the following alcohols,methanol, ethanol, isopropanol, propanol, butanol, sec-butanol andt-butanol. The present recrystallization eliminates the use of thedifficult to remove and potentially harmful solvent DMF. Preferably, thesolvent is isopropanol. By the methods of the present invention, cruderisperidone is recrystallized by dissolving the crude risperidone in asolvent which is hot. Preferably, the solvent is heated to reflux.Preferably the crude risperidone and solvent are present in a ratio ofabout 10 to about 15, more preferably the ratio is about 11 to 13, mostpreferably the ratio is about 11.5 to about 12.5. Preferably the solventis isopropanol. The hot mixture is then filtered hot and allowed to coolwhere upon purified risperidone precipitates. The mixture is filtered byconventional methods to give high purity risperidone with a purity ofabout 99.7 to about 99.8%. The overall yield of the present method ofsynthesis and recrystallization of risperidone is about 60 to about 63%.

The present invention also provides new processes for recrystallizingcrude risperidone from a solvent that is a ketone, such as, acetone. Thepresent recrystallization eliminates the use of the difficult to removeand potentially harmful solvent DMF. Preferably, the solvent is acetone.By the methods of the present invention, crude risperidone isrecrystallized by dissolving the crude risperidone in a ketone, which ishot. Preferably, the ketone is heated to reflux. Preferably the cruderisperidone and solvent are present in a ratio of about 25 to about 40,more preferably the ratio is about 28 to about 32. Preferably thesolvent is acetone. The hot mixture is then filtered hot and allowed tocool where upon purified risperidone precipitates. The mixture isfiltered by conventional methods to give high purity risperidone with apurity of about 99.7 to about 99.8%. The overall yield of the presentmethod of synthesis and recrystallization of risperidone is about 60 toabout 63%.

Risperidone Form A

The present invention also relates to a novel risperidone crystallineform designated Form A and processes for making risperidone Form A.Risperidone Form A is characterized by unique strong powder x-raydiffraction peaks at 14.2±0.2, and 21.3±0.2 degrees two-theta and mediumintensity peaks at 10.6±0.2, 11.410.2, 16.4±0.2, 18.9±0.2, 19.9±0.2,22.5±0.2, 23.3±0.2, 27.6±0.2, 25.4±0.2, and 29.0±0.2 degrees two-theta.

Another aspect of this invention is a method of preparing risperidoneForm A. In the method of preparing risperidone Form A, risperidone FormA is crystallized from risperidone at the reflux temperature of anorganic solvent, such as, DMF, tetrahydrofuran (THF), acetone, benzene,ethyl methyl ketone, n-butanol, methanol, isopropanol, absolute ethanol,acetonitrile, toluene, dimethyl sulfoxide (DMSO), iso-butanol or ethylacetate. By the methods of the present invention, risperidone is addedto in a minimum amount of organic solvent by heating the mixture tofacilitate dissolution of the risperidone. Upon complete dissolution ofthe risperidone, the solution is left to cool to room temperature toinduce the precipitation of risperidone Form A. After the solution hasreached room temperature, it is further cooled in an ice bath and thenfiltered to isolate risperidone Form A. Suitable volumes of solventrequired for the present methods are listed below in Example 11 and inTable 1.

Another aspect of this invention is a method of preparing risperidoneForm A; or a mixture of risperidone Form A and other forms ofrisperidone, including risperidone Form B, by dissolving risperidone indichloromethane and adding cyclohexane or hexane to induceprecipitation. By the methods of the present invention, risperidone isdissolved in dichloromethane in a ratio of about 1 to about 9. Hexane orcyclohexane is then added until a cloudy dispersion is formed. Therisperidone Form A is then isolated by filtration.

Another aspect of this invention is a method of preparing risperidoneForm A by heating risperidone Form B. By the methods of the presentinvention, risperidone Form A is prepared by heating risperidone Form B,or a mixture of risperidone Form A and B at temperatures above roomtemperature, preferably at about 80° C., under either reduced pressureor at atmospheric pressure, for a period of several minutes to severalhours, preferably 16-20 hours. One embodiment of the present method forpreparing risperidone Form A is heating risperidone Form B, or a mixtureof risperidone Form B and risperidone Form A, at 80° C. overnight, underreduced pressure or at atmospheric pressure, and isolating the resultingcrystals of risperidone Form A. An alternative method of preparingrisperidone Form A by heating risperidone Form B includes, heatingrisperidone Form B in a differential scanning calorimeter, at the rateof 5 to 20 degrees per minute, to yield risperidone Form A.

Risperidone Form B

The present invention also relates to a novel crystalline form ofrisperidone, denominated risperidone Form B. Risperidone Form B ischaracterized by unique strong powder x-ray diffraction peaks at14.0±0.2 and 21.7±0.2 degrees two-theta, and medium peaks at 10.8±0.2,11.9±0.2, 12.6±0.2, 17.5±0.2, 18.3±0.2, 19.9±0.2, 21.0±0.2, 21.3±0.2degrees two-theta, and is well distinguished from risperidone Form A.The presence of risperidone Form B in a mixture with risperidone Form Ais detected by the appearance mainly of the strongest peaks at 21.7±0.2,17.5±0.2, 18.4±0.2, and also by the other peaks which appear at11.9±0.2, 12.6±0.2 degrees two theta.

The DSC thermogram of risperidone Form B is characterized by asolid—solid transition to risperidone Form A detected in a smallendotherm at 164° C. followed by a small exotherm and a meltingendotherm of risperidone Form A at 171° C.

Another aspect of this invention is a method of preparing risperidoneForm B by dissolving risperidone in an alcohol having 1 to 4 carbonatoms, followed by the addition of water to facilitate the precipitationof risperidone Form B. Preferably the ratio of risperidone to alcohol isabout 1:7.5 to about 1:9. Preferably the alcohol is ethanol or methanol.

Another aspect of this invention is a method of preparing risperidoneForm B pure or in a mixture with another form of risperidone, such as,risperidone Form A, which includes dissolving risperidone in a hotsolution of aqueous HCl followed by the addition of aqueous Na₂CO₃ toinduce precipitation of risperidone Form B. By the methods of thepresent invention, risperidone is added to 0.5 N HCl in a ratio of about1:6. Water is added in an amount equal to about two thirds the volume ofHCl used. The solution is heated to induce dissolution of therisperidone. Sodium carbonate is then added until a pH of about 8 isreached, to facilitate precipitation. The solution is cooled andrisperidone Form B is isolated by filtration.

Another aspect of this invention is a method of preparing risperidoneForm B pure or in a mixture with another form of risperidone such asrisperidone Form A, wherein risperidone is dissolved in chloroformfollowed by the addition of cyclohexane or hexane to facilitateprecipitation. By the methods of the present invention, risperidone isdissolved in chloroform in a ratio of about 1:6 followed by the additionof hexane of cyclohexane in an amount sufficient to produce a cloudydispersion. The risperidone Form B is then isolated upon filtration.

Risperidone Form E

The present invention also relates to a novel crystalline form ofrisperidone, denominated risperidone Form E. Risperidone Form E ischaracterized by typical strong x-ray peaks at 16.5±0.2, 21.7±0.2degrees two-theta, and medium x-ray peaks at 12.6±0.2, 15.6±0.2,17.0±0.2, 18.4±0.2, 19.1±0.2, 21.3±0.2, 24.0±0.2, 24.9±0.2, 27.0±0.2degrees two-theta

Another aspect of this invention is a method of preparing risperidoneForm E. By the methods of the present invention, risperidone isdissolved in isopropanol in a ratio of about 1 to 12. Water is thenadded until a cloudy dispersion is formed thereby facilitating theprecipitation of risperidone Form E. Risperidone Form E is isolated uponfiltration of the dispersion.

In accordance with the present invention, these new forms of risperidonemay be prepared as pharmaceutical compositions that are particularlyuseful for the management of the manifestations of psychotic disorders.Such compositions comprise one of the new forms of risperidone withpharmaceutically acceptable carriers and/or excipients known to one ofskill in the art.

Preferably, these compositions are prepared as medicaments to beadministered orally, or intravenously. Suitable forms for oraladministration include tablets, compressed or coated pills, dragees,sachets, hard or gelatin capsules, sub-lingual tablets, syrups andsuspensions. While one of ordinary skill in the art will understand thatdosages will vary according to the indication, age of the patient, etc.,generally polymorphic forms of risperidone of the present invention willbe administered at a daily dosage of about 4 to about 16 mg per day, andpreferably about 4 to about 8 mg per day.

EXAMPLES

The present invention will now be further explained in the followingexamples. However, the present invention should not be construed aslimited thereby.

Methods

Conditions for obtaining Powder X-ray Diffraction (PXRD) patterns: Thepowder X-ray diffraction patterns were obtained by methods known in theart using a Philips X-ray powder diffractometer, Phillips Generator TW1830; Goniometer PW3020; MPD Control PW3710; X-Ray tube with Cu targetanode; Monochromator proportional counter; Divergence slits 1°,Receiving slit 0.2 mm, Scatter slit 1°; 40 KV, 30 mA; and Scanning speedstep 0.05 degrees to 2 degrees/min.

The differential scanning calorimeter thermograms were obtained bymethods known in the art using a DSC Mettler 821 Star^(e). The weight ofthe samples was about 3-5 mg. The temperature range of scans was 30°C.-250° C. at a rate of 10C/min. Samples were purged with nitrogen gasat a flow rate of 40 mL/min. Standard 40 μl aluminum crucibles were usedhaving lids with three small holes.

Example 1 Synthesis of Risperidone

Isopropanol (20 mL),3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(Compound II)(“the chlorine derivative”)(2.63 g, 10 mmoles, 1 eq.),6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I)(“thepiperidine derivative”) (2.17 g, 10 mmoles, 1 eq.), sodium carbonate(3.18 g, 30 mmoles, 3 eq.), and potassium iodide (66 mg) were added to a100 mL round bottom flask and stirred with a magnetic stir bar. Theflask was placed in an oil bath at 80° C. and allowed to reflux for 9hours. The flask was then cooled in an ice bath and the contents wasfiltered. The filter cake was washed in the filter with a small amountof isopropanol. The filter cake was then slurried 3 times in 20 mL ofwater and filtered. The resulting slurry was dried to give 3 g ofmaterial in 73% yield. The slurry was recrystallized by dissolving in 37mL of boiling isopropanol, filtered hot and allowed to cool and filteredto give material which had a purity of 99.7% and an overall yield of60%.

Example 2 Synthesis of Risperidone

The same materials and method as in Example 1 with the exception beingthat methyl ethyl ketone (MEK) (15 mL) was used instead of 20 mL ofisopropanol. The flask was put in an oil bath at 79-83° C. overnight,cooled, filtered and washed with acetone and water to give 2.19 g, 53%yield.

Example 3 Synthesis of Risperidone

The same materials and method as in Example 1 with the exception beingthat 20 mL of acetonitrile was used instead of 20 mL of isopropanol. Theflask was put in an oil bath for 17 hours at 79-83° C., then put in thefreezer for 2 hours, filtered, and the filter cake washed with acetoneuntil the filtrate had no color. The filter cake was then slurried in 25mL water 3 times and filtered and dried to give 3.03 g, 74% yield, ofcrude risperidone. The crude risperidone was recrystallized from 35 mLof isopropanol, filtered hot, cooled, filtered and dried to give 2.47 gof risperidone, 60% overall yield, 99.8% pure by HPLC.

Example 4 Synthesis of Risperidone

The same materials and method as in Example 1 with the exception beingthat 20 mL of acetonitrile was used instead of 20 mL of isopropanol. Theflask was put in an oil bath for 17 hours at 79-83° C., then put in thefreezer for 2 hours, filtered, and the filter cake washed with acetoneuntil the filtrate had no color. The filter cake was then slurried in 25mL water 3 times and filtered and dried to give 3.03 g, 74% yield, ofcrude risperidone. The crude risperidone was recrystallized from 75 mLof acetone, filtered hot, cooled, filtered and dried to give 2.25 g ofrisperidone, 60% overall yield, 99.9% pure by HPLC.

Example 5 Synthesis of Risperidone

The same materials and method as in Example 1 with the exception beingthat 20 mL of iso-butanol was used instead of 20 mL of isopropanolfollowed by stirring in an oil bath at 78° C. over night. Risperidonewas isolated in 63% yield.

Example 6 Preparation of Risperidone Form B

Risperidone (5.3 g) was dissolved in chloroform (30 mL). Cyclohexane(280 mL)was slowly added to the solution until a cloudy dispersion wasformed. The suspension was filtered. The filtrate, analyzed by PXRD,contained risperidone Form B. Further heating overnight at 80° C. underreduced pressure produced risperidone Form A, which was confirmed byPXRD analysis.

Example 7 Preparation of Risperidone Form B

Risperidone (5.0 g) was dissolved in 30 mL chloroform. Hexane (250 mL)was added to the solution until a cloudy dispersion was formed. Thesuspension was filtered. The isolated filtrate, analyzed by PXRD,contained risperidone Form B. Further heating of the filtrate overnightat 80° C. under reduced pressure produced risperidone Form A, which wasconfirmed by PXRD analysis.

Example 8 Preparation of Risperidone Form B

Risperidone (5.3 g) was dissolved in 40 ml ethanol. Water (100 mL) wasadded to the solution until a cloudy dispersion was formed. Theresulting suspension was filtered. The isolated filtrate, analyzed byPXRD, contained risperidone Form B. Further heating of the filtrateovernight at 80° C., under reduced pressure, produced risperidone FormA, which was confirmed by PXRD analysis.

Example 9 Preparation of Risperidone Form B

Risperidone (5.0 g) was dissolved in methanol (45 mL). Water (70 ml) wasadded to the solution until a cloudy dispersion was formed. Thesuspension was filtered. The isolated filtrate, analyzed by PXRD,contained risperidone Form B. Further heating of the filtrate overnightat 80° C., under reduced pressure, produced risperidone Form A, whichwas confirmed by PXRD analysis.

Example 10 Preparation of Risperidone Form B in Water

Risperidone (6 g) was dissolved at room temperature in 60 mL of 0.5 NHCl and water (40 mL) was added. The solution was heated in a boilingwater bath and stirred with a magnetic stir bar. Concentrated aqueoussodium carbonate was added portion-wise to the solution to facilitateprecipitation until a pH of approximately 8 was attained. A precipitatewas formed. After cooling to room temperature, the mixture was cooled inan ice bath and filtered to give a mixture of risperidone Form A andrisperidone Form B in an 82% yield.

Example 11 Preparation of Risperidone Form A by Crystallization inOrganic Solvents

Risperidone (6 g) was added portion-wise and dissolved in a minimumamount of solvent by heating in a boiling water bath (about 95° C.).Suitable solvents and the corresponding suitable volumes are listedbelow in Table 1. Solvents having a boiling point lower than 95° C. wereheated to their boiling point. The solutions were left to cool to roomtemperature to facilitate precipitation of risperidone Form A. Themixture was then further cooled in an ice bath and then filtered. Theprecipitate was analyzed by PXRD and found to be risperidone Form A.

TABLE 1 Preparation of Risperidone Form A The volumes of solvents usedper 6 grams of Risperidone DMF:  40 ml iso-butanol:  35 ml THF:  40 mlAcetone: 200 ml Benzene:  26 ml methyl ethyl ketone:  70 ml absoluteethanol:  35 ml n-butanol:  45 ml Methanol:  40 ml Toluene:  45 mlAcetonitrile: 100 ml DMSO: 100 ml ethyl acetate: 150 ml Isopropanol: 100ml

Example 12 Preparation of Risperidone Form A

Risperidone (5.6 g) was dissolved in 50 mL dichloromethane. Cyclohexane(170 mL) was added to the solution until a cloudy dispersion was formed.The resulting suspension was filtered. The isolated filtrate, analyzedby PXRD, contained risperidone Form A and a minor quantity ofrisperidone Form B.

Example 13 Preparation of Risperidone Form A

Risperidone (5.1 g) was dissolved in 30 mL dichloromethane. n-Hexane(150 mL) was added to the solution to facilitate precipitation until acloudy dispersion was formed. The resulting suspension was filtered. Thefiltrate, analyzed by PXRD, contained risperidone Form A and a minorquantity of risperidone Form B.

Example 14 Preparation of Risperidone Form E

Risperidone (5 g ) was dissolved in 60 mL isopropanol. Water (950 mL)was added to the solution to facilitate precipitation until a cloudydispersion was formed. The suspension was filtered. The filtrate,analyzed by PXRD, contained risperidone Form E.

Although certain presently preferred embodiments of the invention havebeen described herein, it will be apparent to those skilled in the artto which the invention pertains that variations and modifications of thedescribed embodiment may be made without departing from the spirit andscope of the invention. Accordingly, it is intended that the inventionbe limited only to the extent required by the appended claims and theapplicable rules of law.

What is claimed is:
 1. Risperidone Form A which is characterized byx-ray powder diffraction peaks at 14.2±0.2, 21.3±0.2 degrees two-theta.2. The risperidone Form A of claim 1 which is further characterized byx-ray powder diffraction peaks at 10.6±0.2, 11.4±0.2, 16.4±0.2,18.9±0.2, 19.9±0.2, 22.5±0.2, 23.3±0.2, 25.4±0.2, 27.6±0.2, 29.0±0.2degrees two-theta.
 3. A risperidone polymorph that is characterized by apowder x-ray diffraction pattern substantially as depicted in FIG.
 1. 4.Risperidone Form B which is characterized by x-ray powder diffractionpeaks at 14.0±0.2 and 21.7±0.2 degrees two-theta.
 5. The risperidoneForm B of claim 4 which is further characterized by x-ray powderdiffraction peaks at 10.8±0.2, 11.9±0.2, 12.6±0.2, 14.0±0.2, 17.5±0.2,18.3±0.2, 19.9±0.2, 21.0±0.2, 21.7±0.2 degrees two-theta.
 6. Arisperidone polymorph that is characterized by a powder x-raydiffraction pattern substantially as depicted in FIG.
 2. 7. RisperidoneForm E which is characterized by x-ray powder diffraction peaks at16.5±0.2, 21.7±0.2 degrees two-theta.
 8. The risperidone Form E of claim7 which is further characterized by x-ray powder diffraction peaks at16.5±0.2, 12.6±0.2, 21.7±0.2, 15.6±0.2, 17.0±0.2, 18.4±0.2, 19.1±0.2,21.3±0.2, 24.0±0.2, 24.9±0.2, 27.0±0.2 degrees two-theta.
 9. Arisperidone polymorph that is characterized by a powder x-raydiffraction to pattern substantially as depicted in FIG.
 3. 10. Aprocess for preparing risperidone Form B comprising the steps of: (a)dissolving risperidone in a water soluble alcohol having 1 to 4 carbonatoms where the ratio of risperidone to alcohol is about 1:7.5 to about1:9; (b) adding water to facilitate precipitation; and (c) isolatingrisperidone Form B.
 11. A process for preparing risperidone Form Bcomprising the steps of: (a) dissolving risperidone in chloroform; (b)adding cyclohexane or hexane to facilitate precipitation; and (c)isolating risperidone Form B.
 12. A process for preparing risperidoneForm B comprising the steps of: (a) dissolving risperidone in an aqueoussolution of HCl; (b) adding aqueous Na₂CO₃ to facilitate precipitation;and (c) isolating risperidone Form B.
 13. A process for preparingrisperidone Form A comprising the steps of: (a) dissolving risperidonein an organic solvent selected from the group consisting ofdimethylformamide, tetrahydrofuran, acetone, benzene, ethyl methylketone, n-butanol, methanol, isopropanol, absolute ethanol,acetonitrile, toluene, dimethyl sulfoxide, iso-butanol, and ethylacetate; (b) heating the solvent to reflux; (c) cooling the solvent tofacilitate precipitation; and (d) isolating risperidone Form A.
 14. Aprocess for preparing risperidone Form A comprising the steps of: (a)dissolving risperidone in dichloromethane; (b) adding cyclohexane orhexane to facilitate precipitation; and (c) isolating risperidone FormA.
 15. A process for preparing risperidone Form E comprising the stepsof: (a) dissolving risperidone in isopropanol where the ratio ofrisperidone to isopropanol is about 1:12; (b) adding water to facilitateprecipitation; and (c) isolating risperidone Form E.
 16. A process forpreparing risperidone Form A comprising the steps of: (a) heatingrisperidone Form B at a temperature of about 250° C. to about 800° C.for a time sufficient to induce to formation of risperidone Form A; and(b) isolating risperidone Form A.
 17. The process of claim 16 whereinthe heating takes place under reduced pressure or at atmosphericpressure.
 18. The process of claim 16 wherein the temperature is about800° C.
 19. The process of claim 16 wherein the time is about 16 toabout 20 hours.